Computational study of the binding orientation and affinity of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-1 considering the protein flexibility by using molecular dynamics and cross-docking

The papain-like protease (PLpro) from zoonotic coronaviruses (CoVs) has been identified as a target with an essential role in viral respiratory diseases caused by Severe Acute Respiratory Syndrome-associated coronaviruses (SARS-CoVs). The design of PLpro inhibitors has been proposed as an alternative to developing potential drugs against this disease. In this work, 67 naphthalene-derived compounds as noncovalent PLpro inhibitors were studied using molecular modeling methods. Structural characteristics of the bioactive conformations of these inhibitors and their interactions at the SARS-CoV-1 PLpro binding site were reported here in detail, taking into account the flexibility of the protein residues. Firstly, a molecular docking protocol was used to obtain the orientations of the inhibitors. After this, the orientations were compared, and the recurrent interactions between the PLpro residues and ligand chemical groups were described (with LigRMSD and interaction fingerprints methods). In addition, efforts were made to find correlations between docking energy values and experimentally determined binding affinities. For this, the PLpro was sampled by using Gaussian Accelerated Molecular Dynamics (GaMD), generating multiple conformations of the binding site. Diverse protein conformations were selected and a cross-docking experiment was performed, yielding models of the 67 naphthalene-derived compounds adopting different binding modes. Representative complexes for each ligand were selected to obtain the highest correlation between docking energies and activities. A good correlation (R (2) = 0.948) was found when this flexible docking protocol was performed.